Gene therapy with the angiogenesis inhibitor endostatin in an orthotopic lung cancer murine model.
Angiogenesis plays an important role in the growth of solid tumors. To date, no information has been acquired on the effectiveness of gene therapy in the orthotopic lung cancer model of syngeneic immunocompetent mice treated with an angiogenesis inhibitor. Here, we report the establishment of such a model in which Lewis lung carcinoma (LL/2) cell suspensions were orthotopically inoculated into the lung parenchyma of C57BL/6 mice, which were also injected with a recombinant adenoviral vector delivering the human endostatin gene (Ad-hE). We found that orthotopic implantation of LL/2 cells into the lung parenchyma produced a solitary tumor nodule in the lung followed by remote mediastinal lymph node metastasis. Conditioned medium from Ad-hE-transfected LL/2 cells apparently inhibited proliferation of human umbilical vein endothelial cells (HUVECs). The level of endostatin protein in serum could be identified by enzyme-linked immunosorbent assay. Treatment with Ad-hE resulted in inhibition of tumor growth and prolongation of survival time of tumor-bearing mice. Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed. Furthermore, the finding of angiogenesis inhibition was also supported by measuring the number of circulating endothelial cells (CECs). Apoptotic cells were found to be increased within tumor tissues from mice treated with Ad-hE. In addition, treatment with Ad-hE combined with cis-diamminedichloroplatinum(II) (cisplatin) enhanced antitumor activity. These observations provide further evidence of the antitumor effect of endostatin gene therapy, and may be of importance for further exploration of potential application of this combined approach in the treatment of human lung cancer as well as other solid tumors.
Ning
Tao
T
Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China.
Yan
Xi
X
Lu
Ze-Jun
ZJ
Wang
Guo-Ping
GP
Zhang
Ning-Gang
NG
Yang
Jin-Liang
JL
Jiang
Sha-Sha
SS
Wu
Yang
Y
Yang
Li
L
Guan
Yong-Song
YS
Luo
Feng
F
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D043169:Endostatins / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000235:genetics
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011994:Recombinant Proteins